The present invention relates to processes for making 2-amino-2-imidazoline derivatives, guanidine derivatives, and 2-amino-3,4,5,6-tetrahydropyrimidine derivatives (all herein collectively described as "2-amino-2-derivatives"). Such derivatives are useful for the treatment of many medical disorders including, for example, respiratory disorders, ocular disorders, gastrointestinal disorders, nasal decongestion, hypertension, migraine, disorders associated with sympathetic nervous system activity, and substance abuse. One of the most widely known of these derivatives is clonidine, an alpha-2-adrenoreceptor agonist and antihypertensive agent. Iopidine is also a known alpha-2-adrenoreceptor agonist useful in reducing intraocular pressure: ##STR1## Clonidine, disclosed in U.S. Pat. No. 3,202,660 (1965) to Boehringer, Ing.; Iopidine, disclosed in U.S. Pat. No. 4,517,199 (1985) to Alcon; Timmermans, P. B. M. W. M., de Jonge, A., Thoolen, M. J. M. C., Wilffert, B., Batink, H., van Zwieten, P. A., "Quantitative Relationships between .alpha.-Adrenergic Activity and Binding Affinity of .alpha.-Adrenoceptor Agonists and Antagonists", Journal of Medicinal Chemistry Vol. 27 (1984) pp. 495-503; Physician's Desk Reference (50th ed., 1996).
Therapeutic indications of alpha-2-adrenoreceptor agonists have been discussed in the literature. Ruffolo, R. R., Nichols, A. J., Stadel, J. M., and Hieble, J. P., "Pharmacologic and Therapeutic Applications of Alpha-2-Adrenoceptor Subtypes", Annual Review of Pharmacology & Toxicology Vol. 32 (1993) pp. 243-279.
Further information regarding alpha adrenergic receptors, agonists and antagonists, in general, are disclosed in the following references: Timmermans, P. B. M. W. M., Chiu, A. T., and Thoolen, M. J. M. C., "12.1 .alpha.-Adrenergic Receptors", Comprehensive Medicinal Chemistry, Vol. 3, Membranes & Receptors, P. G. Sammes & J. B. Taylor, eds., Pergamon Press (1990), pp. 133-185; Timmermans, P. B. M. W. M., and van Zwieten, P. A., ".alpha.-Adrenoceptor Agonists and Antagonists", Drugs of the Future, Vol. 9, No. 1, (January, 1984), pp. 41-55; Megens, A. A. H. P., Leysen, J. E., Awouters, F. H. L., and Niemegeers, C. J. E., "Further Validation of in vivo and in vitro Pharmacological Procedures for Assessing the .alpha..sub.1 and .alpha..sub.2 -Selectivity of Test Compounds: (2) .alpha.-Adrenoceptor Agonists", European Journal of Pharmacology, Vol. 129 (1986), pp. 57-64; Timmermans, P. B. M. W. M., de Jonge, A., Thoolen, M. J. M. C., Wilffert, B., Batink, H., van Zwieten, P. A., "Quantitative Relationships between .alpha.-Adrenergic Activity and Binding Affinity of .alpha.-Adrenoceptor Agonists and Antagonists", Journal of Medicinal Chemistry, Vol. 27 (1984) pp. 495-503; van Meel, J. C. A., de Jonge, A., Timmermans, P. B. M. W. M., and van Zwieten, P. A., "Selectivity of Some Alpha Adrenoceptor Agonists for Peripheral Alpha-1 and Alpha-2 Adrenoceptors in the Normotensive Rat", The Journal of Pharmacology and Experimental Therapeutics, Vol. 219, No. 3 (1981), pp. 760-767; Chapleo, C. B., et. al., "Effect of 1,4-Dioxanyl Substitution on the Adrenergic Activity of Some Standard .alpha.-Adrenoreceptor Agents", European Journal of Medicinal Chemistry, Vol. 24 (1989), pp. 619-622; Chapleo, C. B., et. al., "Heteroaromatic Analogues of the .alpha..sub.2 -Adrenoreceptor Partial Agonist Clonidine", Journal of Medicinal Chemistry, Vol. 32 (1989), pp. 1627-1630; Clare, K. A., Scrutton, M. C., and Thompson, N. T., "Effects of .alpha..sub.2 -Adrenoceptor Agonists and of Related Compounds on Aggregation of, and on Adenylate Cyclase Activity in, Human Platelets", British Journal of Pharmacology, Vol. 82 (1984), pp. 467-476; U.S. Pat. No. 3,890,319 issued to Danielewicz, Snarey, and Thomas, Jun. 17, 1975; U.S. Pat. No. 5,091,528 issued to Gluchowski, Feb. 25, 1992; U.S. Pat. No. 5,478,858 issued to Cupps and Bogdan, Dec. 26, 1995; and U.S. Pat. No. 5,541,210 issued to Cupps and Bogdan, Jul. 30, 1996.
In the art, 2-amino-2-derivatives have been synthesized according to many different methods. U.S. Pat. No. 4,398,028 issued to Neumann, Aug. 9, 1983; Chapleo, C., et. al., "Heteroaromatic Analogues of the .alpha..sub.2 -Adrenoreceptor Partial Agonist Clonidine", Journal of Medicinal Chemistry, Vol. 32 (1989) pp. 1627-1630; U.S. Pat. No. 5,130,441 issued to Gluchowski, Jul. 14, 1992; U.S. Pat. No. 5,478,858 issued to Cupps and Bogdan, Dec. 26, 1995.
For example, the synthesis of clonidine analogs involves the reaction of 2-thiomethyl-2-imidazoline with an aromatic primary amine in the presence of a large excess of pyridine. However, the literature cites very low yields in this reaction. See Chapleo, C., et. al., "Heteroaromatic Analogues of the .alpha..sub.2 -Adrenoreceptor Partial Agonist Clonidine", Journal of Medicinal Chemistry, Vol. 32 (1989) pp. 1627-1630.
Alternative syntheses of 2-amino-2-derivatives have been performed. However, of further disadvantage in these syntheses is the time-consuming, costly, multiple steps required by these syntheses, and/or the use of mercuric or other transition metal reagents which can result in the presence of toxic impurities. U.S. Pat. No. 4,398,028 issued to Neumann, Aug. 9, 1983; U.S. Pat. No. 5,478,858 issued to Cupps and Bogdan, Dec. 26, 1995.
Still further, other synthetic preparations of 2-amino-2-derivatives have been performed. U.S. Pat. No. 5,130,441 issued to Gluchowski, Jul. 14, 1992. Gluchowski found that yields in the formation of 2-amino-2-imidazolines could be improved over the Chapleo procedure by coupling an aromatic primary amine with an imidazoline sulfonic acid. However, yield improvements in Gluchowski were only moderate. Further, this synthesis required the low yielding preparation of an imidazoline sulfonic acid intermediate.
It is apparent from the art that higher yielding, more economical methods of preparing 2-amino-2-derivatives would be advantageous. It has been surprisingly discovered that the disadvantages of the literature syntheses of these compounds may be overcome by coupling a primary amine or its salts with an acylated 2-thio-substitued-2-imidazoline, -amidine, or -tetrahydropyrimidine intermediate in the presence of a proton source to give the desired 2-amino-2-derivative in one step. Yields in this reaction are significantly higher than those reported in Chapleo. The reaction is also more favorable than the Neumann and Cupps procedures because it overcomes lengthy syntheses and avoids the use of transition metal reagents.
Further, the present invention overcomes the deficiency of the Gluchowski synthesis. The present invention utilizes, not a sulfonic acid, but rather an acylated 2-thio-substitited-2-imidazoline, -amidine, or -tetrahydropyrimidine as the intermediate in the synthesis of 2-amino-2-derivatives. Generally, acylated, 2-thio-substituted-2-imidazolines are known. However, the known syntheses of acylated 2-thiomethyl-2-imidazolines provide low yields. Kohn, H., et. al., "Syntheses and Pharmacological Activity of Substituted Imidazolinethiones and Thioimidazolines", Journal of Medicinal Chemistry, Vol. 20 (1977) pp. 158-160; Kohn, H., et. al., "Syntheses and Spectral Properties of Substituted Imidazolidones and Imidazolines", Journal of Organic Chemistry, Vol. 42 (1977) pp. 941-948. It has been surprisingly discovered that acylated 2-thio-substituted-2-imidazolines, -amidines, and -tetrahydropyrimidines can be prepared in a two-step, one-pot procedure in high yields. This procedure renders the synthesis of acylated 2-thio-substituted-2-derivatives higher yielding, easier, and less time consuming than the procedure in the Kohn reference.
It has therefore now been discovered that 2-amino-2-imidazoline, guanidine, and 2-amino-3,4,5,6-tetrahydropyrimidine derivatives may be conveniently synthesized in high yields by preparing the corresponding acylated 2-thio-substituted-2-derivative in a two-step, one-pot procedure in high yields and by further reacting this isolated derivative with the appropriate amine or its salts in the presence of a proton source. The present process allows for the preparation of 2-amino-2-imidazolines, guanidines, and 2-amino-3,4,5,6-tetrahydropyrimidines under reaction conditions that eliminate the need for lengthy, costly, or multiple low yielding steps, and highly toxic reactants. This process allows for improved yields and product purity and provides additional synthetic flexibility for the preparation of these classes of molecules.
In particular, the preferred processes of the present invention provide a new methodology that is especially suited for the scale-up and manufacture of 2-amino-2-derivatives. The processes utilize commercially-available, low-cost starting materials. The acylated 2-thio-substituted-2-imidazoline, -amidine, or -tetrahydropyrimidine intermediate and the corresponding 2-amino-2-derivative can often be obtained by direct precipitation, thus avoiding the typical extraction and evaporation procedures which are encountered in the literature procedures.